Publications by authors named "Jingjing Ye"

117 Publications

Autophagosome Trafficking.

Adv Exp Med Biol 2021 ;1208:67-77

Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.

Autophagy is a major intracellular degradation/recycling system that ubiquitously exists in eukaryotic cells. Autophagy contributes to the turnover of cellular components through engulfing portions of the cytoplasm or organelles and delivering them to the lysosomes/vacuole to be degraded. The trafficking of autophagosomes and their fusion with lysosomes are important steps that complete their maturation and degradation. In cells such as neuron, autophagosomes traffic long distances along the axon, while in other specialized cells such as cardiomyocytes, it is unclear how and even whether autophagosomes are transported. Therefore, it is important to learn more about the processes and mechanisms of autophagosome trafficking to lysosomes/vacuole during autophagy. The mechanisms of autophagosome trafficking are similar to those of other organelles trafficking within cells. The machinery mainly includes cytoskeletal systems such as actin and microtubules, motor proteins such as myosins and the dynein-dynactin complex, and other proteins like LC3 on the membrane of autophagosomes. Factors regulating autophagosome trafficking have not been widely studied. To date the main reagents identified for disrupting autophagosome trafficking include: 1. Microtubule polymerization reagents, which disrupt microtubules by interfering with microtubule dynamics, thus directly influence microtubule-dependent autophagosome trafficking 2. F-actin-depolymerizing drugs, which inhibit autophagosome formation, and also subsequently inhibit autophagosome trafficking 3. Motor protein regulators, which directly affect autophagosome trafficking.
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http://dx.doi.org/10.1007/978-981-16-2830-6_5DOI Listing
July 2021

Validation of the Chinese version of the Short-Form Health Literacy in Dentistry (HeLD) scale.

Community Dent Oral Epidemiol 2021 Jul 9. Epub 2021 Jul 9.

Department of Social Psychology, Zhou Enlai School of Government, Nankai University, Tianjin, China.

Objectives: As an important part of health literacy, oral health literacy has been adapted to dental practice and research. The 14-item short version of the Health Literacy in Dentistry (HeLD) scale demonstrated excellent reliability, validity and precision when tested among English-speaking populations. However, an appropriate and reliable assessment of this scale in other language contexts remains lacking. The reliability and validity of the Chinese version of HeLD (HeLD-C) for the Chinese population must therefore be examined.

Methods: The short version of HeLD was translated into Chinese, and one item was deleted because of its unsuitability for the Chinese healthcare system. The psychometric properties of HeLD-C were evaluated in a sample of 404 Chinese participants aged from 19 to 72 years. The item selection analyses were performed by comparing the difference of each item between the high- and low-score groups. The internal consistency reliability was assessed using the Cronbach's alpha coefficient. Construct validity was assessed using exploratory structural equation modelling. For the criterion validity, correlations between the HeLD-C and the criterion validity scales, including the eHealth Literacy Scale (eHEALS), oral hygiene maintenance habits, and oral health status were tested using Pearson's correlation.

Results: Results of item selection reveal significant differences among all items between the high- and low-score groups (Ps < .001). The internal consistency reliability of HeLD-C was measured using Cronbach's α (0.92), whereas its construct validity was measured using χ [df] (3.30), comparative fit index (0.95), Tucker-Lewis index (0.94), root mean square error of approximation (0.08), and standardized root mean square residual (0.05). The criterion validity analyses show that HeLD-C is correlated with the criterion validity scales, including eHEALS, oral hygiene maintenance habits and oral health status (Ps < .001).

Conclusions: Chinese version of HeLD is a reliable and valid instrument for measuring the oral health literacy of the Chinese adult population.
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http://dx.doi.org/10.1111/cdoe.12675DOI Listing
July 2021

Practical Considerations and Recommendations for Master Protocol Framework: Basket, Umbrella and Platform Trials.

Ther Innov Regul Sci 2021 Jun 23. Epub 2021 Jun 23.

Global Statistics and Data Sciences, BeiGene, Fulton, MD, 20759, USA.

Master protocol, categorized as basket trial, umbrella trial or platform trial, is an innovative clinical trial framework that aims to expedite clinical drug development, enhance trial efficiency, and eventually bring medicines to patients faster. Despite a clear uptake on the advantages in the concepts and designs, master protocols are still yet to be widely used. Part of that may be due to the fact that the master protocol framework comes with the need for new statistical designs and considerations for analyses and operational challenges. In this article, we provide an overview of the master protocol framework, unify the definitions with some examples, review the statistical methods for the designs and analyses, and focus our discussions on some practical considerations and recommendations of master protocols to help practitioners better design and implement such studies.
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http://dx.doi.org/10.1007/s43441-021-00315-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220876PMC
June 2021

Complex Metal Nanostructures with Programmable Shapes from Simple DNA Building Blocks.

Adv Mater 2021 Jul 4;33(29):e2100381. Epub 2021 Jun 4.

Molecular Biophysics Group, Peter Debye Institute for Soft Matter Physics, Universität Leipzig, 04103, Leipzig, Germany.

Advances in DNA nanotechnology allow the design and fabrication of highly complex DNA structures, uisng specific programmable interactions between smaller nucleic acid building blocks. To convey this concept to the fabrication of metallic nanoparticles, an assembly platform is developed based on a few basic DNA structures that can serve as molds. Programming specific interactions between these elements allows the assembly of mold superstructures with a range of different geometries. Subsequent seeded growth of gold within the mold cavities enables the synthesis of complex metal structures including tightly DNA-caged particles, rolling-pin- and dumbbell-shaped particles, as well as T-shaped and loop particles with high continuity. The method further supports the formation of higher-order assemblies of the obtained metal geometries. Based on electrical and optical characterizations, it is expected that the developed platform is a valuable tool for a self-assembly-based fabrication of nanoelectronic and nanooptic devices.
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http://dx.doi.org/10.1002/adma.202100381DOI Listing
July 2021

Development of selective bispecific Wnt mimetics for bone loss and repair.

Nat Commun 2021 05 31;12(1):3247. Epub 2021 May 31.

Surrozen, Inc., South San Francisco, CA, USA.

The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis.
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http://dx.doi.org/10.1038/s41467-021-23374-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167098PMC
May 2021

Using Z-score to optimize population-specific DDH screening: a retrospective study in Hangzhou, China.

BMC Musculoskelet Disord 2021 Apr 12;22(1):344. Epub 2021 Apr 12.

Department of Ultrasound, The Children's Hospital, Zhejiang University School of Medicine, Binsheng Road 3333#, Hangzhou, 310052, China.

Background: DDH (Developmental Dysplasia of the Hip) screening can potentially avert many morbidities and reduce costs. The debate about universal vs. selective DDH ultrasonography screening in different countries revolves to a large extent around effectiveness, cost, and the possibility of overdiagnosis and overtreatment. In this study, we proposed and evaluated a Z-score enhanced Graf method to optimize population-specific DDH screening.

Methods: A total of 39,710 history ultrasonography hip examinations were collected to establish a sex, side specific and age-based Z-scores model using the local regression method. The correlation between Z-scores and classic Graf types was analyzed. Four thousand two hundred twenty-nine cases with follow-up ultrasonographic examinations and 5284 cases with follow-up X-ray examinations were used to evaluate the false positive rate of the first examination based on the subsequent examinations. The results using classic Graf types and the Z-score enhanced types were compared.

Results: The Z-score enhanced Graf types were highly correlated with the classic Graf's classification (R = 0.67, p < 0.001). Using the Z-scores ≥2 as a threshold could reduce by 86.56 and 80.44% the false positives in the left and right hips based on the follow-up ultrasonographic examinations, and reduce by 78.99% false-positive cases based on the follow-up X-ray examinations, respectively.

Conclusions: Using an age, sex and side specific Z-scores enhanced Graf's method can better control the false positive rate in DDH screening among different populations.
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http://dx.doi.org/10.1186/s12891-021-04216-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042719PMC
April 2021

Sequential Pull-Down Purification of DNA Origami Superstructures.

Small 2021 04 16;17(17):e2007218. Epub 2021 Mar 16.

Molecular Biophysics Group, Peter Debye Institute for Soft Matter Physics, Universität Leipzig, 04103, Leipzig, Germany.

Higher-order superstructures of individual DNA origami building blocks are frequently used in DNA nanotechnology in order to increase the structure dimensions and complexity. Here, a purification method is presented to specifically enrich a fully assembled superstructure out of an excess of substructures. The approach is based on pull-down reactions with magnetic beads, where superstructures are captured via an anchor strand on a specific terminus and then become separated from terminus-free structures. By carrying out several pull-down reactions sequentially on different termini, the full superstructures that possess all termini become finally enriched. The approach is demonstrated by purifying linear origami superstructures with up to nine monomers by two-sided pull-down reactions and a T-shaped superstructure in a three-sided pull-down reaction. In all cases, high recovery yields and purities are obtained. A crucial prerequisite for the sequential pull-down scheme is the establishment of highly specific, orthogonal sequence sets for capture, and anchor strands. It is expected that the introduced approach provides a useful and universal method to purify complex DNA origami superstructures with high specificity and yield and this way allows the massive parallel fabrication of nanostructures at high homogeneity.
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http://dx.doi.org/10.1002/smll.202007218DOI Listing
April 2021

The novel interaction mode among centromere sub-complex CENP-O/P/U/Q/R.

J Mol Recognit 2021 Aug 3;34(8):e2892. Epub 2021 Mar 3.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

The kinetochore is essential for the accurate segregation of sister chromosome in the eukaryote cell. Among the kinetochore subunits, five proteins CENP-O/P/U/Q/R form a stable complex, referred to as CENP-O class, and are required for proper kinetochore function. Although the function and structure of yeast COMA complex (CENP-O/P/U/Q homologs) have been revealed extensively, the assembly mechanism and detail interactions among human CENP-O class are significantly different and remain largely unclear. Here, we identified the fragment (residues 241-360) of CENP-U and the C-terminal half of CENP-Q are essential to form a hetero-complex and interact with CENP-O/P sub-complex in vitro. We for the first time showed that CENP-R does not directly interact with CENP-O/P in vitro, but indeed interact with CENP-U and CENP-Q. Furthermore, both the N- and C-terminus of CENP-R are required for the interaction with CENP-U and CENP-Q. Our research pinpointed a novel interaction pattern that might shed light on the assembly mechanism of vertebrate CENP-O class.
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http://dx.doi.org/10.1002/jmr.2892DOI Listing
August 2021

Genome-wide landscape of mRNAs, microRNAs, lncRNAs, and circRNAs in hemorrhagic shock-induced ALI/ARDS in rats.

J Trauma Acute Care Surg 2021 05;90(5):827-837

From the Trauma Medicine Center (Z.W., P.C., J.Z., P.Z., X.C., B.J., W.H., T.W.), Peking University People's Hospital, Key Laboratory of Trauma and Neural Regeneration (Peking University), National Center for Trauma Medicine of China; Department of Central Laboratory and Institute of Clinical Molecular Biology (J.Y.), Peking University People's Hospital; Basic Medical Research Center (W.M.), the Sixth Medical Center of the General Hospital of the Chinese People's Liberation Army; and Department of Physiology and Pathophysiology (M.Z.), School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China.

Background: Hemorrhagic shock (HS) can develop into multiple organ dysfunction syndrome, among which acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) usually lead to poor outcomes. The underlying molecular mechanisms of HS-induced ALI/ARDS remain unclear. This study sought to investigate gene expression profiles and predict competing endogenous RNA (ceRNA) regulatory networks in an HS-induced ALI/ARDS preclinical model.

Methods: Sprague Dawley rats were subjected to a fixed volume of hemorrhage (HS, 40% estimated total blood volume) or not (sham) randomly. After 8 hours of observation, left lung tissue was harvested to evaluate lung injury. Right lung was collected for RNA sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed and the long noncoding RNA (lncRNA)/circular RNA (circRNA)-microRNA (miRNA)-messenger RNA (mRNA) linkages were predicted using the ceRNA theory. Quantitative real-time polymerase chain reaction was used to validate the RNA sequencing findings.

Results: Hemorrhagic shock lungs showed noticeable ALI/ARDS features, and 437 mRNAs, 31 miRNAs, 734 lncRNAs, and 29 circRNAs were differentially expressed. In Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, the differentially expressed transcripts were enriched in the following terms: the metabolic pathways, signal transduction pathways, necroptosis, DNA damage recognition and repair, inflammatory cell migration and chemotaxis, the NOD-like receptor signaling pathway, the Janus kinase/signal transducer and activator of transcription signaling pathway, the mitogen-activated protein kinase signaling pathway, the phosphatidylinositol-3-kinase/protein kinase B signaling pathway, and so on. Also, this study identified lncRNA-miRNA-mRNA linkages with 12 lncRNAs, 5 miRNAs, 15 mRNAs, and circRNA-miRNA-mRNA linkages with 10 circRNAs, 16 miRNAs, 39 mRNAs. These networks might play important regulatory roles.

Conclusion: This is the first high-throughput analysis of gene expression profiles in HS-induced ALI/ARDS. It shows that metabolism, cell signaling, DNA damage and repair, and necroptosis-related RNAs altered, and inflammatory response-associated RNAs and pathways have pivotal roles in HS-induced ALI/ARDS progression. It also prompts some important RNAs and regulatory networks for future research.

Level Of Evidence: Basic science article.
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http://dx.doi.org/10.1097/TA.0000000000003119DOI Listing
May 2021

MDMX/MDM4 is highly expressed and contributes to cell growth and survival in anaplastic large cell lymphoma.

Leuk Lymphoma 2021 07 11;62(7):1563-1573. Epub 2021 Feb 11.

Department of Pathology, University of Crete, Medical School, Heraklion, Greece.

We hypothesized that murine double minute X (MDMX), a negative p53-regulator, may be involved in dysfunctional p53-signaling in anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive and ALK-negative, characterized frequently by non-mutated . By western blot analysis, MDMX was highly expressed in ALK + ALCL and expressed at variable levels in ALK- ALCL cell lines. By immunohistochemistry, high MDMX levels were observed more frequently in ALK + ALCL (36/46; 78%), compared with ALK- ALCL tumors (12/29; 41%) ( < .0018, Mann-Whitney-test). analysis showed -amplification in 1 of 13 (8%) ALK- ALCL tumors, and low-level MDMX copy gains in 2 of 13 (15%) ALK- ALCL and 3 of 11 (27%) ALK + ALCL tumors. MDMX-pharmacologic inhibition or -mediated -silencing were associated with activated p53 signaling, growth inhibition and apoptotic cell death in ALCL cells, providing evidence that targeting MDMX may provide a new therapeutic approach for ALCL patients with .
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http://dx.doi.org/10.1080/10428194.2021.1876871DOI Listing
July 2021

Nutritional status in patients of mandibular osteoradionecrosis: A single-institution experience.

Oral Dis 2020 Dec 28. Epub 2020 Dec 28.

Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China.

Background: Mandibular osteoradionecrosis (ORN) is a devastating complication secondary to the radiotherapy of head and neck cancer. The nutritional status of ORN patients is compromised, but remains rarely studied. We aimed to evaluate the overall nutritional status of patients with ORN and explore the risk factors behind poor nutrition.

Methods: This is a single-institution cross-sectional study. Patients diagnosed with ORN were consecutively recruited in a tertiary teaching hospital from July 2017 to August 2019. Multiple laboratory markers and physical indicators were examined to profile their nutritional status. The potential risk factors of poor nutrition were explored by logistic regression.

Results: A total of 107 patients with ORN were recruited. Among them, almost all patients (95.3%) had at least one laboratory marker lower than the normal physiological range. A total of 40 (37.5%) patients were categorized as undernutrition, who had lower serum albumin (mean difference: 1.8 ± 0.8 g/L; p = .02), prealbumin (mean difference: 26.8 ± 10.8 mg/L; p = .02), and BMI (3.8 ± 0.4 kg/m ; p < .0001) compared to patients of normal nutrition. Notably, the multivariate logistic regression indicated that patients with semi-liquid diet had 14.41 (95% CI: 3.03-68.54, p = .001) times; patients with liquid diet had 5.70 (95% CI: 1.55-20.98, p = .009) times more likely to be in undernutrition, as compared to patients with regular diets.

Conclusions: This is the first study characterizing the poor nutritional status in ORN patients. Patients having semi-liquid or liquid diets tended to have poorer nutritional status. The nutritional status of ORN patients should be underlined for professional nutritional supports so as to enhance their quality of life. More studies are warranted.
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http://dx.doi.org/10.1111/odi.13762DOI Listing
December 2020

Ferritin as a key risk factor for nonalcoholic fatty liver disease in children with obesity.

J Clin Lab Anal 2021 Feb 28;35(2):e23602. Epub 2020 Nov 28.

National Clinical Research Center for Child Health, Hangzhou, China.

Background: The association between serum ferritin and nonalcoholic fatty liver disease (NAFLD) in children with obesity is not clear. This study was designed to investigate whether serum ferritin can be an independent predictor for NAFLD.

Methods: According to the hepatic ultrasound results, a total of 347 children with obesity were enrolled in this study. Among them, 95 patients with NAFLD and 95 without NAFLD were matched for gender, age, blood pressure and body mass index, the odds ratios (OR) and 95% confidence intervals (CI) for the association of ferritin and the risk of NAFLD were analyzed.

Results: After propensity score matching, ferritin values of the patients with NAFLD were significantly higher than those without NAFLD group. Alanine aminotransferase and ferritin were strongly associated with NAFLD in multivariate stepwise logistic regression analysis. The medium and high levels of ferritin increased risk of NAFLD, and the adjusted ORs were 3.298 (95% CI:1.326-8.204), 7.322 (95% CI:2.725-19.574) across the ferritin concentration tertiles after adjustment for confounders. Ferritin was shown to be the best predictor for NAFLD with sensitivity and specificity of 60.0% and 77.9%, respectively, area under the curve was 0.733.

Conclusion: The results show that serum ferritin can usefully be considered as a predictor of NAFLD in children with obesity.
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http://dx.doi.org/10.1002/jcla.23602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891541PMC
February 2021

A review of the experience with pediatric written requests issued for oncology drug products.

Pediatr Blood Cancer 2021 02 27;68(2):e28828. Epub 2020 Nov 27.

Division of Biostatistics IX (DBIX), Office of Biostatistics (OB), Office of Translational Sciences (OTS), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland.

Background: Pediatric anticancer drug development has numerous challenges. The Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) were passed to address pediatric drug development deficiencies in general. Until recently, the requirements for pediatric evaluation of most oncology products developed for adult cancers have been waived. Because children typically do not have the same type of cancers, which occur commonly in adults, or the indication or drug had been granted an orphan designation, PREA therefore has had no impact. Pediatric studies for labeling updates are largely done through BPCA by a written request (WR) issued by the Food and Drug Administration (FDA). Because the cancers that occur in pediatric and adult populations do not share the same etiology or natural history, there are limited opportunities to extrapolate adult efficacy and safety to the pediatric population. The characteristics of individual pediatric studies included in WRs have varied greatly over time.

Procedure: In this study, we searched WRs that were issued by the FDA since 2001. We found 40 such requests issued for oncology drugs and biologics, which had been accepted by sponsors.

Results: Clinical trials included in 23 of the WRs have been concluded, 19 have resulted in exclusivity, and three drugs that were studied have been approved for use in pediatric populations. Herein, we present the spectrum of WRs from a regulatory, study design, dosing, formulation, analysis plan, evidentiary standard of efficacy, and safety perspective.

Conclusions: This provides information on requests issued in the past nearly 20 years and studies that are completed. As WRs have provided the only regulatory mechanism to assure pediatric cancer drug development, this can potentially provide insight on how pediatric cancer drug development may change in the future.
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http://dx.doi.org/10.1002/pbc.28828DOI Listing
February 2021

[Artificial intelligence technology in cardiac auscultation screening for congenital heart disease: present and future].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 Oct;49(5):548-555

The Heart Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Regional Medical Center for Children, Hangzhou 310052, China.

The electronic stethoscope combined with artificial intelligence (AI) technology has realized the digital acquisition of heart sounds and intelligent identification of congenital heart disease, which provides objective basis for heart sound auscultation and improves the accuracy of congenital heart disease diagnosis. At the present stage, the AI based cardiac auscultation technique mainly focuses on the research of AI algorithms, and the researchers have designed and summarized a variety of effective algorithms based on the characteristics of cardiac audio data, among which the mel-frequency cepstral coefficients (MFCC) is the most effective one, and widely used in the cardiac auscultation. However, the current cardiac sound analysis techniques are based on specific data sets, and have not been validated in clinic, so the performance of algorithms need to be further verified. The lack of heart sound data, especially the high-quality, standardized, publicly available heart sound database with disease labeling, further restricts the development of heart sound diagnostic analysis and its application in screening. Therefore, expert consensus is necessary in establishing an authoritative heart sound database and standardizing the heart sound auscultation screening process for congenital heart disease. This paper provides an overview of the research and application status of auscultation algorithm and hardware equipment based on AI in auscultation screening of congenital heart disease, and puts forward the problems to be solved in clinical application of AI auscultation screening technology.
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http://dx.doi.org/10.3785/j.issn.1008-9292.2020.10.01DOI Listing
October 2020

NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma.

Cancer Lett 2021 01 19;497:178-189. Epub 2020 Oct 19.

Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China. Electronic address:

The NLRP3 inflammasome plays a pro-tumorigenic role in various malignancies. However, its potential role in lymphomagenesis remains unclear. In this study, we identified an immunosuppressive state in patients with diffuse large B cell lymphoma (DLBCL), which was characterized by markedly elevated interleukin (IL)-18 levels in lymphoma tissues and positive correlation with programmed death ligand 1 (PD-L1) expression. Furthermore, NLRP3 inflammasome activation in DLBCL cell lines upregulated PD-L1 and reduced the proportion of cytotoxic T cells. NLRP3 inflammasome blockade in vivo suppressed lymphoma growth and ameliorated anti-tumor immunity by downregulating PD-L1 in the tumor microenvironment and decreasing the proportion of PD-1/TIM-3-expressing T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Further in vivo studies revealed IL-18 as the main effector cytokine involved in the negative regulation of anti-lymphoma immunity. Interestingly, NLRP3 blockers combined with anti-PD-L1 treatment exerted antagonistic effects during lymphoma therapy. Altogether, our findings indicate that NLRP3 inflammasome promotes immunosuppression by modulating PD-L1 and immune cells. Accordingly, this study highlights the prognostic and therapeutic values of the NLRP3 inflammasome in lymphoma.
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http://dx.doi.org/10.1016/j.canlet.2020.10.024DOI Listing
January 2021

Genetic polymorphisms and expression of NLRP3 inflammasome-related genes are associated with Philadelphia chromosome-negative myeloproliferative neoplasms.

Hum Immunol 2020 Oct - Nov;81(10-11):606-613. Epub 2020 Sep 25.

Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Jinan, Shandong, PR China. Electronic address:

Inflammation plays a crucial role in the initiation, progression and prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which could be clinically subdivided into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasomes affect inflammatory diseases and carcinomas by excessive production of cytokines. To investigate a possible association of NLRP3 inflammasome signaling with MPN, we investigated the expression of selected inflammasome-related genes from bone marrow cells of 67 MPN patients as well as gene polymorphisms in NLRP3 (rs35829419), NF-κB1 (rs28362491), CARD8 (rs2043211), IL-1β (rs16944), and IL-18 (rs1946518). It showed that inflammasome-related genes (NLRP3, NF-κB1, CARD8, IL-1β, and IL-18) were highly expressed in BM cells from MPN patients and the increased expression was associated with JAK2 mutation, white blood cell counts and splenomegaly. Analysis of genetic polymorphisms in 269 MPN patients and 291 healthy controls demonstrated that NF-κB1 (rs28362491) was associated with MPN and increased expression of NF-κB1, NLRP3 and IL-1β. This research provided novel biomarkers and potential targets for MPN.
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http://dx.doi.org/10.1016/j.humimm.2020.09.001DOI Listing
June 2021

Casting of Gold Nanoparticles with High Aspect Ratios inside DNA Molds.

Small 2020 10 2;16(39):e2003662. Epub 2020 Sep 2.

Molecular Biophysics group, Peter Debye Institute for Soft Matter Physics, Universität Leipzig, Leipzig, 04103, Germany.

DNA nanostructures provide a powerful platform for the programmable assembly of nanomaterials. Here this approach is extended to synthesize rod-like gold nanoparticles in a full DNA controlled manner. The approach is based on DNA molds containing elongated cavities. Gold is deposited inside the molds using a seeded-growth procedure. By carefully exploring the growth parameters it is shown that gold nanostructures with aspect ratios of up to 7 can be grown from single seeds. The highly anisotropic growth is in this case controlled only by the rather soft and porous DNA walls. The optimized seeded growth procedure provides a robust and simple routine to achieve continuous gold nanostructures using DNA templating.
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http://dx.doi.org/10.1002/smll.202003662DOI Listing
October 2020

TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1.

J Exp Clin Cancer Res 2020 Aug 14;39(1):158. Epub 2020 Aug 14.

Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.

Background: Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. Therefore, unraveling molecular networks that drive this process constitutes an urgent unmet need. Herein, we aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance.

Methods: The expression levels of TNFAIP8 were assessed in AML patients and cell lines by RT-qPCR and western blots. The transcriptional regulation of TNFAIP8 was analyzed with luciferase reporter assay and ChIP followed by RT-qPCR. Functional experiments were conducted to evaluate the effects of TNFAIP8 on apoptosis, drug sensitivity and proliferation of AML cells. Potential effects of TNFAIP8 on the activation of extracellular signal-regulated kinase (ERK) pathway were detected by western blots. CoIP and P21-activated kinase (PAK) pull-down assay were performed to ascertain the upstream target. The overall effects of TNFAIP8 on AML were examined in murine models.

Results: Upregulated TNFAIP8 expression was first confirmed in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was then identified to contribute to its aberrant expression. Through manipulating TNFAIP8 expression, we described its role in protecting AML cells from apoptosis induced by chemotherapeutic agents and in promoting drug resistance. Notably, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the ERK signaling pathway, through an interaction with Rac family small GTPase 1 (Rac1). In addition, in vivo experiments confirmed that TNFAIP8 suppression lowered leukemia infiltration and improved survival.

Conclusion: Our data provide a molecular basis for the role of TNFAIP8 in chemoresistance and progression of AML and highlight the unique function of TNFAIP8 as an attractive therapeutic target.
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http://dx.doi.org/10.1186/s13046-020-01658-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427779PMC
August 2020

An Enzyme-Responsive Prodrug with Inflammation-Triggered Therapeutic Drug Release Characteristics.

Macromol Biosci 2020 09 30;20(9):e2000116. Epub 2020 Jun 30.

Center of Advanced Elastomer Materials, State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) for relieving inflammatory reactions can lead to severe side effects. It is of great importance to configure new dosing strategies for alleviating the side effects of NSAIDs. In this work, an enzyme-responsive anti-inflammatory prodrug capable of generating indomethacin upon the trigger of inflammation is developed. A monomer is first prepared after the esterification of carboxyl groups of indomethacin by hydroxyl groups of N-(2-hydroxyethyl) acrylamide. Then, a polymer prodrug, with indomethacin linked through ester bonds on the side chain, is synthesized by free radical polymerization of the monomer. The therapeutic drug component can be triggered to release from the prodrug under the stimulation of cholesterol esterase, mimicking the inflammation environment. On the contrary, there is only a small amount of drug released in the absence of the enzyme. Therefore, the drug can be triggered to release under the stimulation of an environment mimicking inflammation. Furthermore, the in vitro studies at the cellular level indicate that the enzyme-responsive prodrug can efficiently relieve inflammatory responses induced by lipopolysaccharide in RAW264.7 macrophage cells while indicating no cytotoxicity.
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http://dx.doi.org/10.1002/mabi.202000116DOI Listing
September 2020

A Bayesian approach in design and analysis of pediatric cancer clinical trials.

Pharm Stat 2020 11 14;19(6):814-826. Epub 2020 Jun 14.

Division of Biometrics V, Office of Biostatistics, Office of Translational Sciences, Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.

It is well recognized that cancer drug development for children and adolescents has many challenges, from biological and societal to economic. Pediatric cancer consists of a diverse group of rare diseases, and the relatively small population of children with multiple, disparate tumor types across various age groups presents a significant challenge for drug development programs as compared to oncology drug development programs for adults. Due to the different types of cancers, limited opportunities exist for extrapolation of efficacy from adult cancer indications to children. Thus, innovative study designs including Bayesian statistical approaches should be considered. A Bayesian approach can be a flexible tool to formally leverage prior knowledge of adult or external controls in pediatric cancer trials. In this article, we provide in a case example of how Bayesian approaches can be used to design, monitor, and analyze pediatric trials. Particularly, Bayesian sequential monitoring can be useful to monitor pediatric trial results as data accumulate. In addition, designing a pediatric trial with both skeptical and enthusiastic priors with Bayesian sequential monitoring can be an efficient mechanism for early trial cessation for both efficacy and futility. The interpretation of efficacy using a Bayesian approach is based on posterior probability and is intuitive and interpretable for patients, parents and prescribers given limited data.
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http://dx.doi.org/10.1002/pst.2039DOI Listing
November 2020

Identification of HMG-box family establishes the significance of SOX6 in the malignant progression of glioblastoma.

Aging (Albany NY) 2020 05 10;12(9):8084-8106. Epub 2020 May 10.

Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu 241001, China.

Glioblastoma multiforme (GBM) is the most malignant neuroepithelial primary brain tumor and its mean survival time is 15 months after diagnosis. This study undertook to investigate the genome-wide and transcriptome-wide analyses of human high mobility group box (HMG-box) TF (transcript factor) families / HOX, TOX, FOX, HMG and SOX gene families, and their relationships to GBM. According to the TCGA-GBM profile analysis, differentially expressed HOX, FOX, HMG and SOX gene families (62 DEmRNA) were found in this study. We also analyzed DEmRNA (HMG-box related genes) co-expressed eight DElncRNA in GBM, and constructed a ceRNA network analysis as well. We constructed 50 DElncRNA-DEmiRNA-DEmRNA (HMG-box related genes) pairs between GBM and normal tissues. Then, risk genes SOX6 and SOX21 expression were correlated with immune infiltration levels in GBM. SOX6 also had a strong association with MAPT, GSK3B, FYN and DPYSL4, suggesting that they might be functional members in GBM.
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http://dx.doi.org/10.18632/aging.103127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244032PMC
May 2020

Sonographic diagnosis of an unusual cervical foreign body that migrated through a pyriform sinus fistula.

J Clin Ultrasound 2021 Feb 7;49(2):141-144. Epub 2020 Apr 7.

Department of Ultrasound, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.

Foreign body ingestion is common in the pediatric population. We report a case of ingestion of sunflower seeds that migrated in the left neck through a pyriform sinus fistula, ultrasound plays an important role in preoperative diagnosis and is a useful tool for diagnosing both pyriform sinus fistulas and radiolucent foreign bodies.
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http://dx.doi.org/10.1002/jcu.22841DOI Listing
February 2021

Myeloid-Derived Suppressor Cells and γδT17 Cells Contribute to the Development of Gastric MALT Lymphoma in -Infected Mice.

Front Immunol 2019 28;10:3104. Epub 2020 Jan 28.

Department of Hematology, Qilu Hospital of Shandong University, Jinan, China.

-induced chronic inflammation and immune disorders are closely associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Myeloid-derived suppressor cells (MDSCs) exhibit strong immunosuppressive properties and promote the growth of various solid tumors. However, the role of MDSCs in the development of MALT lymphoma has not been elucidated so far. We detected significant infiltration and enrichment of MDSCs in patients with MALT lymphoma, as well in -infected mouse model of gastric MALT lymphoma. In addition, the expression of arginase-1 and inducible nitric oxide synthase was significantly elevated both in gastric MALT lymphoma tissues and -infected stomach. Persistent infection closely reproduced the development of gastric MALT lymphoma and was accompanied by increased numbers of γδT17 cells. Accumulation of γδT17 cells was also validated in the human gastric MALT lymphoma tissues. Furthermore, the elevated cytokines interleukin-23 and interleukin-1β, as well as chemokines CCL20/CCR6, may be involved in the accumulation of γδT17 cells and the subsequent immunosuppression. These findings highlight the role of MDSCs and γδT17 cells in immune dysregulation during gastric MALT lymphoma development and their potential as therapeutic targets.
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http://dx.doi.org/10.3389/fimmu.2019.03104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998799PMC
November 2020

LncRNA Dnmt3aos regulates Dnmt3a expression leading to aberrant DNA methylation in macrophage polarization.

FASEB J 2020 04 13;34(4):5077-5091. Epub 2020 Feb 13.

Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institutes, Wannan Medical College, Wuhu, PR China.

Long non-coding RNAs (lncRNAs) play key roles in various biological processes. However, the roles of lncRNAs in macrophage polarization remain largely unexplored. In this study, thousands of lncRNAs were identified that are differentially expressed in distinct polarized bone marrow-derived macrophages. Among them, Dnmt3aos (DNA methyltransferase 3A, opposite strand), as a known lncRNA, locates on the antisense strand of Dnmt3a. Functional experiments further confirmed that Dnmt3aos were highly expressed in M(IL-4) macrophages and participated in the regulation of Dnmt3a expression, and played a key role in macrophage polarization. The DNA methylation profiles between the Dnmt3aos knockdown group and the control group in M(IL-4) macrophages were determined by MeDIP-seq technique for the first time, and the Dnmt3aos-Dnmt3a axis-mediated DNA methylation modification-regulated macrophage polarization- related gene IFN-γ was identified. Our study will help to enrich our knowledge of the mechanism of macrophage polarization.
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http://dx.doi.org/10.1096/fj.201902379RDOI Listing
April 2020

Oxycodone preemptive analgesia after endoscopic plasma total adenotonsillectomy in children: A randomized controlled trial.

Medicine (Baltimore) 2020 Feb;99(6):e19004

Department of Anesthesiology.

Background: Endoscopic tonsillectomy is associated with postoperative pain. Postoperative pain management remains to be improved in children. We aimed to investigate oxycodone preemptive analgesia in children undergoing endoscopic plasma total adenotonsillectomy.

Methods: 166 children with adenotonsillar hypertrophy were recruited at Wuhan Children's Hospital between 08/2016 and 03/2017. They were randomly assigned to receive SPOA (postoperative sufentanil), SPEA+SPOA (preemptive sufentanil and postoperative sufentanil), and OPEA+SPOA (preemptive oxycodone and postoperative sufentanil). The primary endpoint was serum c-fos levels. The secondary endpoints were the response entropy (RE) value, Pediatric Anesthesia Emergence Delirium (PAED) score, FLACC score, and adverse events.

Results: c-fos mRNA levels were increased significantly after surgery in the SPOA and SPEA+SPOA groups (P < .05). Postoperatively, c-fos mRNA levels were higher in the SPOA group compared with the OPEA+SPOA group (P = .044). The RE values increased in all groups after surgery (P < .05). At extubation, RE values were higher in the SPOA group compared with the SPEA+SPOA and OPEA+SPOA groups (P < .05). The PAED scores were higher in the SPOA group compared with the OPEA+SPOA group (P = .045). In the SPOA group, the FLACC scores were decreased at 24 h after surgery vs 4 hours (P = .044). Prediction probability (Pk) values indicated that RE and c-fos mRNA levels were quantitative predictors for early postoperative stress reaction after surgery.

Conclusions: The subanalgesic dose of oxycodone (0.1 mg/kg) as preemptive analgesia could improve pain after endoscopic plasma total adenotonsillectomy in children.
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http://dx.doi.org/10.1097/MD.0000000000019004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015576PMC
February 2020

Structural insights into the intramolecular interactions of centromere protein CENP-I.

J Mol Recognit 2020 07 3;33(7):e2837. Epub 2020 Feb 3.

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

In mitosis, the accurate segregation of sister chromosomes relies on kinetochore, a multiple subunits complex assembled on centromere of each sister chromosome. As a core component of inner kinetochore, CENP-I plays important functions to mediate kinetochore assembly and supports the faithful chromosome segregation. The structures of the N-terminus and C-terminus of CENP-I homologs in complex with CENP-H/K have been reported, respectively. Unfortunately, the intramolecular interactions of CENP-I are poorly understood, and how CENP-I interacts with CENP-M remains unknown. Here, we verified a unique helix α11, which forms the intramolecular interactions with N-terminal HEAT repeats in fungal CENP-I. Deletion of the helix α11 exposed the hydrophobic surface and resulted in the in vitro protein aggregation of N-terminal HEAT repeats of fungal CENP-I. The corresponding helix and its intramolecular interaction are highly conserved in human CENP-I. Deletion of the corresponding helix in human CENP-I dramatically reduced the functional activity to interact with CENP-H and CENP-M. Mutations of the conserved residues on the helix in human CENP-I significantly weakened the binding to CENP-M, but not CENP-H, in HeLa cells. Therefore, our findings for the first time unveiled a conserved helix of CENP-I, which is important for the intramolecular interaction and function, and would be helpful for understanding the structure basis of how CENP-I mediates the kinetochore assembly during cell cycle and mitosis.
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http://dx.doi.org/10.1002/jmr.2837DOI Listing
July 2020

The Relationship between Circulating ANGPTL8/Betatrophin Concentrations and Adult Obesity: A Meta-Analysis.

Dis Markers 2019 22;2019:5096860. Epub 2019 Oct 22.

Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, Jiangsu 212001, China.

In this study, we evaluated the relationship between circulating betatrophin levels and obesity. Obesity is a common public health problem that is increasing globally. Betatrophin, a newly identified protein, is predominantly expressed in white and brown fat tissues and in the liver. Growing evidence suggests that betatrophin plays a pivotal role in metabolism, including the synthesis and degradation of lipids in cells, and adipocyte differentiation. Previous studies have assessed the association between circulating betatrophin levels and obesity; however, this relationship remains unclear. Therefore, our study is aimed at examining the impact of betatrophin on obesity using a meta-analysis of the current evidence. We performed a meta-analysis to quantify the relationship between betatrophin levels and obesity. A literature search was conducted through the EMBASE, Web of Science, and MEDLINE databases. Retrieved studies were screened, without any language restrictions to identify relevant literature published up to December 2018. Observational studies, in which the association between circulating concentrations of betatrophin and obesity was evaluated, were considered suitable for the systematic review. Of the 65 manuscripts retrieved, 9 datasets from 6 studies, involving 681 participants, detected an association between circulating betatrophin and obesity. Circulating betatrophin levels of obese subjects were higher than those of nonobese subjects (random - effects weighted mean difference (WMD) = 0.250 g/mL, 95% CI: 0.048-0.451, = 94.8%, = 0.015), yet with significant between-study heterogeneity. This heterogeneity appeared to be modified by glycemic status but not by age, the ELISA kits used, sample source, or body mass index. The high circulating betatrophin concentration may directly increase the risk of obesity in adults. Betatrophin may serve as a therapeutic target for obesity in adults.
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http://dx.doi.org/10.1155/2019/5096860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854917PMC
April 2020

Polyvinyl Alcohol-Stabilized Liquid Metal Hydrogel for Wearable Transient Epidermal Sensors.

ACS Appl Mater Interfaces 2019 Dec 6;11(50):47358-47364. Epub 2019 Dec 6.

Center of Advanced Elastomer Materials, State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials , Beijing University of Chemical Technology , Beijing 100029 , P.R. China.

Wearable epidermal sensors are attracting growing interests in human activity monitoring and flexible touch display, but they are still limited by the poor self-healing property and the difficult dissolvable feature. Herein, we report polyvinyl alcohol (PVA)-stabilized liquid metal particles (LMPs) (PVA-LMPs) hydrogels with excellent self-healing performance and the dissolvable feature for wearable epidermal sensors, constructed by dispersing LMPs of eutectic gallium and indium into the borate-modified PVA polymer networks. Interestingly, the PVA-LMPs hydrogels exhibited excellent electrically and mechanically self-healing ability. Moreover, the PVA-LMPs hydrogel can be fabricated as epidermal sensors, which can accurately monitor the human activities. Additionally, the epidermal sensors are dissolvable, showing an attractive feature for on demand transient electronics. It is demonstrated that the hydroxyl groups of PVA can stabilize LMPs via hydrogen-bonding interactions. Furthermore, the dynamic cross-linking bonds between hydrogels and LMPs can rupture and coalesce reversibly in the hydrogel network, which endow the hydrogels with both electrically and mechanically self-healing ability. This work shows the potential of constructing next-generation multifunctional hydrogel-based epidermal sensors for human activity monitoring, wearable healthcare diagnosis, portable electronics, and robot tactile systems.
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http://dx.doi.org/10.1021/acsami.9b16675DOI Listing
December 2019

Gas6 attenuates lipopolysaccharide‑induced TNF‑α expression and apoptosis in H9C2 cells through NF‑κB and MAPK inhibition via the Axl/PI3K/Akt pathway.

Int J Mol Med 2019 Sep 12;44(3):982-994. Epub 2019 Jul 12.

Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Therapeutic agents used to treat sepsis‑induced cardiac dysfunction are designed to suppress tumor necrosis factor (TNF)‑α release and inhibit cell apoptosis. Exogenous administration of growth arrest‑specific 6 (Gas6) exerts several biological and pharmacological effects; however, the role of Gas6 in sepsis‑induced myocardial dysfunction remains unclear. In this study, H9C2 cardiomyocytes were stimulated with LPS (10 µg/ml) to mimic septic cardiac dysfunction and Gas6 (100 ng/ml) was applied exogenously. Subsequently, mitogen‑activated protein kinase (MAPK) and nuclear factor (NF)‑κB activation, TNF‑α expression, and apoptosis in the presence or absence of TP‑0903 (15 nM) and Wortmannin (3 nM) were evaluated. The morphological alterations of H9C2 cells were visualized by phase‑contrast microscopy. Cell viability was determined using the Cell Counting kit 8 assay and lactate dehydrogenase release, and TNF‑α release was analyzed by ELISA analysis. Cell apoptosis was analyzed by flow cytometry and TUNEL assay. Nuclear morphological alterations were detected by Hoechst staining and caspase‑3 activity was measured using biochemical methods. The expression levels of Bax and Bcl‑2, and the phosphorylation and expression levels of Axl, Akt, IκB‑α, p65, c‑Jun N‑terminal protein kinase (JNK), extracellular signal‑regulated kinase (ERK) and p38 were determined by western blotting. Furthermore, immunofluorescence analysis was performed to visualize translocation of NF‑κB p65. The results demonstrated that Gas6 suppressed TNF‑α release and inhibited cell apoptosis, and attenuated nuclear factor (NF)‑κB and mitogen‑activated protein kinase (MAPK) activation via the Axl/PI3K/Akt pathway. Furthermore, the cardioprotective properties of Gas6 on the suppression of LPS‑induced TNF‑α release and apoptosis were abolished by treatment with TP‑0903 (an Axl inhibitor) and Wortmannin (a PI3K inhibitor). Pretreatment with TP‑0903 and Wortmannin abrogated the effects of Gas6 on phosphorylated‑IκB‑α, IκB‑α, NF‑κB, ERK1/2, JNK and p38 MAPK. These findings suggested that activation of Axl/PI3K/Akt signaling by Gas6 may inhibit LPS‑induced TNF‑α expression and apoptosis, as well as MAPK and NF‑κB activation.
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http://dx.doi.org/10.3892/ijmm.2019.4275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657963PMC
September 2019

Miro2 Regulates Inter-Mitochondrial Communication in the Heart and Protects Against TAC-Induced Cardiac Dysfunction.

Circ Res 2019 09 28;125(8):728-743. Epub 2019 Aug 28.

From the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, People's Republic of China (Y.C., C.X., J.Y., X.Z., S.J., X.Q., C.Z., R.L., L.W., Y.L., L.L., M.Z.).

The constrained mitochondria in cardiomyocytes communicate with each other, through mitochondrial kissing or nanotunneling, forming a dynamically continuous network to share content and transfer signals. However, the molecular mechanism of cardiac inter-mitochondrial communication is unclear. To determine the molecular mechanism underlying the robust inter-mitochondrial communication and its pathophysiological relevance in the heart. By mitochondria-targeted expressing the photoactivatable green fluorescent protein, we revealed that most mitochondrial nanotubes bridge communicating mitochondrial pairs were associated with microtubules. Miro2 (mitochondrial Rho GTPase), the outer mitochondrial membrane protein which usually mediates mitochondrial transport within cells, accompanied with mitochondrial nanotubes along microtubules in adult cardiomyocytes. Adenovirus mediated expression of Miro2 in cardiomyocytes accelerated inter-mitochondrial communication through increasing mitochondrial nanotunneling and mitochondrial kissing between adjacent mitochondrial pairs. In transverse aortic constriction-induced hypertrophic mouse hearts Miro2 protein was declined, accompanied with decreased inter-mitochondrial communication. Miro2 transgenic mice showed ameliorated cardiac function, increased mitochondrial nanotube formation and inter-mitochondrial communication, and improved mitochondrial function after transverse aortic constriction. E3 ubiquitin ligase Parkin was increased in transverse aortic constriction mouse hearts and phenylephrine stimulation-induced hypertrophic cardiomyocytes. Inhibition of proteasome blocked phenylephrine-induced decrease of Miro2, and Parkin overexpression led to the decrease of Miro2. Mitochondrial Miro2 expression levels regulate inter-mitochondrial communication along microtubules in adult cardiomyocytes, and degradation of Miro2 through Parkin-mediated ubiquitination contributes to impaired inter-mitochondrial communication and cardiac dysfunction during hypertrophic heart diseases.Visual Overview: An online visual overview is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315432DOI Listing
September 2019
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